The protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function. Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems.
The Raf family of serine/threonine kinases include three members: C-Raf (or Raf-1), B-Raf and A-Raf. Activating alleles of B-Raf have been identified in ˜70% of melanomas, 40% of papillary thyroid carcinoma, 30% of ovarian low-grade carcinoma, and 10% of colorectal cancers. Most B-Raf mutations are found within the kinase domain, with a single substitution (V600E) accounting for 80%. The mutated B-Raf proteins activate Raf-MEK-ERK pathway either via elevated kinase activity toward MEK or via activating C-Raf. The B-Raf inhibitor in the present combination therapy inhibits cellular processes involving B-Raf kinase by blocking the signal cascade in these cancer cells and ultimately inducing stasis and/or death of the cells. B-Raf inhibitors useful in the present combinations are generally and specifically described in published PCT patent application WO2011/025927, which is hereby incorporated by reference.
There are three classes of PI3-Kinases (PI3K). The class I enzymes consist of heterodimers having a regulatory (p85) domain and a catalytic (p110) subunit, of which there are four isoforms: p110α, p110β, p110δ and p110γ. The α and β isoforms are ubiquitously expressed; a is linked upstream mainly to receptor tyrosine kinases, whereas β can mediate signals from both G-protein-coupled receptors and from receptor tyrosine kinases. The δ and γ isoforms are expressed primarily in lymphocytes and play important roles in the regulation of immune responses.
A gain of function in PI3K signaling is common in many types of human cancer and include inactivation of the PTEN tumor suppressor gene, amplification/overexpression or activating mutations of some receptor tyrosine kinases (e.g. erbB3, erbB2, EGFR), amplification of genomic regions containing AKT, amplification of PIK3CA (the gene encoding p110α) and mutations in p110α. More than 30% of various solid tumor types were recently found to contain mutations of PIK3CA. From these mutation frequencies, PIK3CA is one of the most commonly mutated genes identified in human cancers. PI3K inhibitors useful in the present method, which have inhibitory activity for the α-isoform of PI3-kinases, are described in WO2010/029082 which is hereby incorporated by reference.
EGFRs are transmembrane receptors present on cell membranes. They have an extracellular binding component, a transmembrane component and an intracellular tyrosine kinase component. EGFRs play an important role in controlling normal cell growth, apoptosis and other cellular functions. Deregulation of EGFR activity can lead to continual or abnormal activation of the receptors causing unregulated cell division.
Epidermal growth factor receptor inhibitors are known in the art. Typically, they are either small molecule tyrosine kinase inhibitors, such as erlotinib and gefitinib, or monoclonal antibodies. Anti-EGFR monoclonal antibodies, such as cetuximab and panitumumab, are especially useful EGFR inhibitors for use in the present invention. Cetuximab, its preparation and use for treating proliferative diseases is disclosed in U.S. Pat. No. 6,217,866, which is here incorporated by reference. Panitumumab, its preparation and use for treating proliferative diseases is disclosed in U.S. Pat. No. 6,235,883, which is here incorporated by reference